EP0011609B1 - Xanthinderivate und pharmazeutische Zusammensetzung zur Verwendung für die Behandlung chronischer Verstopfungen der Atemwege und von Herzkrankheiten - Google Patents

Xanthinderivate und pharmazeutische Zusammensetzung zur Verwendung für die Behandlung chronischer Verstopfungen der Atemwege und von Herzkrankheiten Download PDF

Info

Publication number
EP0011609B1
EP0011609B1 EP79850091A EP79850091A EP0011609B1 EP 0011609 B1 EP0011609 B1 EP 0011609B1 EP 79850091 A EP79850091 A EP 79850091A EP 79850091 A EP79850091 A EP 79850091A EP 0011609 B1 EP0011609 B1 EP 0011609B1
Authority
EP
European Patent Office
Prior art keywords
derivatives
disease
filtered
treatment
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP79850091A
Other languages
English (en)
French (fr)
Other versions
EP0011609A3 (en
EP0011609A2 (de
EP0011609B2 (de
Inventor
Per Gunnar Kjellin
Carl Göran August Persson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Draco AB
Original Assignee
Draco AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=20336144&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP0011609(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Draco AB filed Critical Draco AB
Priority to AT79850091T priority Critical patent/ATE2999T1/de
Priority to DE8181106977T priority patent/DE2967002D1/de
Publication of EP0011609A2 publication Critical patent/EP0011609A2/de
Publication of EP0011609A3 publication Critical patent/EP0011609A3/xx
Application granted granted Critical
Publication of EP0011609B1 publication Critical patent/EP0011609B1/de
Publication of EP0011609B2 publication Critical patent/EP0011609B2/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3

Definitions

  • the present invention relates to a novel group of compounds which have a relaxing effect on the bronchial smooth muscle and pharmaceutical compositions containing them for use in treating chronic obstructive airway disease (COAD) or cardiac disease.
  • COAD chronic obstructive airway disease
  • Theophylline and various salts thereof are used in the treatment of chronic obstructive airway disease (COAD) and cardiac disease.
  • COAD chronic obstructive airway disease
  • Major therapeutic effects of theophylline are to relax bronchial smooth muscle and stimulate heart muscle.
  • the major drawback with theophylline therapy is that the drug with a significant frequency produces toxic side-effects; most common are nausea and gastric distress, most serious are convulsions, which may lead to death.
  • the present invention relates to the treatment of COAD and cardiac disease with xanthine derivatives which have a favourable ratio between bronchodilator potency and toxic potency compared to theophylline.
  • the present invention relates to the use of a compound of the formula and therapeutically acceptable salts thereof, wherein R is the group
  • Formula I includes the compound of the formula
  • Formula 1 includes also the compound of the formula D 4031
  • the present invention includes pharmaceutically acceptable salts of compounds of formula (1) with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts is meant salts the cations of which are relatively innocuous to the animal organism when used in therapeutic doses so that the beneficial pharmacological properties of the parent compounds of general formula (1) are not vitiated by side effects ascribable to those cations.
  • Suitable salts include the alkali metal, e.g. sodium and potassium, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, e.g.
  • glycine ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol, 2-amino-2-(hydroxymethyl)-propane-1,3-diol and 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.
  • compositions may be prepared by the reaction together of stoichiometric quantities of a compound of formula (1) and the appropriate base, that is to say, a base as described immediately hereinbefore, for example at an elevated temperature, with or without an appropriate solvent, preferably followed by recrystallisation from an appropriate solvent, for example a hydroxylic solvent, e.g. water, of the salt so formed.
  • a base as described immediately hereinbefore, for example at an elevated temperature
  • an appropriate solvent preferably followed by recrystallisation from an appropriate solvent, for example a hydroxylic solvent, e.g. water, of the salt so formed.
  • the compounds of the present invention will normally be administered orally, rectally, nasally, sublingually, by injection or by inhalation in the form of a pharmaceutical preparation comprising the active ingredient in the form of the original compound or optionally in the form of a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier which may be a solid, semi-solid or liquid diluent or an ingestible capsule, and such preparations comprise a further aspect of the invention.
  • a pharmaceutically acceptable carrier which may be a solid, semi-solid or liquid diluent or an ingestible capsule, and such preparations comprise a further aspect of the invention.
  • the active substance will comprise between 0.1 and 99% by weight of the preparation, for example 0.5 and 20% for preparations intended for injection and between 0.1 and 50% for preparations intended for oral administration.
  • the active ingredient may be mixed with a solid, pulverulent carrier, for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, laminaria powder or citrus pulp powder, a cellulose derivative, polyvinylpyrrolidone or gelatine and also may include lubricants such as magnesium or calcium stearate or a Carbowax@ or other polyethylene glycol-waxes and compressed to form tablets or cores for dragées.
  • a solid, pulverulent carrier for example lactose, saccharose, sorbitol, mannitol, a starch such as potato starch, corn starch, amylopectin, laminaria powder or citrus pulp powder, a cellulose derivative, polyvinylpyrrolidone or gelatine and also may include lubricants such as magnesium or calcium stearate or a Carbowax@ or other polyethylene glycol-waxes
  • the cores may be coated, for example with concentrated sugar solutions which may contain gum arabic, talc and/or titanium dioxide, or alternatively with a film forming agent dissolved in easily volatile organic solvents or other suitable solvent or mixtures of organic solvents.
  • Dyestuffs can be added to these coating for example, to distinguish between different contents of active substance.
  • the active substance may be admixed with a Carbowax@ or a suitable oil as e.g. sesam oil, olive oil, or arachis oil.
  • Hard gelatine capsules may contain granulates of the active substance with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylpectin), cellulose derivatives, polyvinylpyrrolidone or gelatine, and may also include magnesium stearate or stearic acid as lubricants.
  • solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylpectin), cellulose derivatives, polyvinylpyrrolidone or gelatine, and may also include magnesium stearate or stearic acid as lubricants.
  • a compound of the invention may also be formulated as a sustained action dosage form using suitable excipients.
  • suitable excipients Different methods may be used for the availability control e.g. diffusion process and ion exchange. Methods using the diffusion process may be exemplified by products involving coated granules or particles, matrix imbedded drug and slightly soluble forms.
  • Effervescent powders are prepared by mixing the active ingredient with non-toxic carbonates or hydrogen carbonates of e.g. sodium, potassium or calcium, such as calcium carbonate, potassium carbonate and potassium hydrogen carbonate, solid, non-toxic acids such as tartaric acid, ascorbic acid, and citric acid, and for example aroma.
  • non-toxic carbonates or hydrogen carbonates e.g. sodium, potassium or calcium, such as calcium carbonate, potassium carbonate and potassium hydrogen carbonate, solid, non-toxic acids such as tartaric acid, ascorbic acid, and citric acid, and for example aroma.
  • Liquid preparations for oral application may be in the form of elixirs, syrups or suspensions, for example solutions containing from about 0.1% to 20% by weight of active substance, sugar and a mixture of ethanol, water, glycerol, propylene glycol and optionally aroma, saccharine and/or carboxymethylcellulose as a dispersing agent.
  • injection preparations may comprise an aqueous solution or suspension of the active substances according to the invention, desirably in a concentration of 0.5-10%, and optionally also a stabilizing agent and/or buffer substances in aqueous solution. Dosage units of the solution may advantaqeously be enclosed in ampoules.
  • the dosage at which the active ingredients are administered may vary within a wide range and will depend on various factors such as for example the individual requirements of each patient.
  • a suitable oral dosage range is from 50 to 1000 mg given 1-4 times a day.
  • a suitable dosage range at parenteral administration is from 20 to 500 mg.
  • compositions containing the active ingredients may suitably be formulated so that they provide doses within these ranges either as single dosage units or as multiple dosage units.
  • Guinea-pigs of both sexes were killed by a blow on the head and bled.
  • the trachea was removed and cut spirally yielding one or two preparations.
  • The. tracheal preparations were mounted in organ baths containing Krebs solution maintained at 37°C and bubbled with carbogen (95% O 2 +5% CO 2 ).
  • Isometric tension reflecting mainly activity in circular tracheal muscle was recorded by means of a force displacement transducer. Initial tension was set at 0.5 g which was the approximate basal tension kept during the experiment. Evaluation of relaxant effects was done when the preparations had contracted to a stable tension by the addition of carbocholine 0.1 ug/ml to the bath.
  • EC 50 values i.e.
  • Theophylline (TA) is one by definition and a value larger than one indicates that the drug is more potent than the ophylline.
  • the hearts were immediately removed and perfused with oxygenated Krebs solution at 37° according to Langendorff.
  • the heart was mounted in a thermostatically controlled organ bath (25 ml) containing Krebs solution.
  • a saline-filled, open-end polyethylene catheter was inserted into the right ventricle through the pulmonary artery.
  • the catheter was fixed to the pulmonary artery by a ligature just above the valvular plane. It was connected to a pressure transduser (P23 AC), making it possible to record changes in intraventricular pressure. From these, the contraction frequency was obtained.
  • Drugs were given as single bolus injections into the perfusion solution.
  • mice Male NMRI mice, weighing 20-26 g, starved for 8 h were used.
  • the compounds dissolved in 0.5 M NaOH and 0.85% NaCI-solution (pH 10.6-12.1) were administered as follows:
  • bronchodilator potency ratios and the i.v. acute toxicity ratios the relation between therapeutic ratios bronchodilator dose: toxic dose for theophylline and each compound can be calculated.
  • Table 1 The therapeutic ratio or index indicates the safety of a drug. It is clear from Table 1 that the 3-alkyl-xanthines of the invention, D 4028 in particular, have a better therapeutic index (both for bronchodilatation and cardiac stimulating) than theophylline. It is further indicated by findings in the toxicity studies that 3-alkyl-xanthines do not produce convulsions which theophylline does.
  • the compounds D 4028, D 4030, and D 4031 have been found to be without convulsive effects and to have a better therapeutic index than theophylline, i.e. in comparison with theophylline they are less likely to produce toxic side effects when used as bronchodilators or as cardiac stimulants.
  • Frrigen is used to denote the halogenated hydrocarbons.
  • Frigen 114 is 1,2-dichloro-1,1,2,2-tetrafluorethane
  • Frigen 113 is 1,1-difluoro-2,2-dichlorotri- fluorotrichloroethane
  • Frigen 11 is trichloromonofluoromethane
  • Frigen 12 is dichlorodifluoromethane.
  • Myglyol denotes a triglyceride of saturated vegetable oils. Or a pulver aerosol where the active substance is mixed with lactose.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Pulmonology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (4)

1. Pharmazeutisches Präparat zur Verwendung bei der Behandlung von chronischer obstruktiver Erkrankung der Luftwege oder von Herzleiden umfassend als aktives Ingredienz eine wirksame Menge einer Verbindung der Formel
Figure imgb0018
oder eines therapeutisch akzeptablen Salzes derselben, worin R -CH2CH2CH3, -CH2CH2CH2CH3 oder -CH2CH(CH3)2 bedeutet, in Verbindung mit einem pharmazeutisch akzeptablen Träger.
2. Pharmazeutisches Präparat nach Anspruch 1, worin das aktive Ingredienz eine Verbindung der Formel I ist, worin R -CH2CH2CH3 bedeutet.
3. Verbindung der Formel
Figure imgb0019
oder ein therapeutisch akzeptables Salz derselben, worin R -CH2CH2CH3, -CH2CH2CH2CH3 oder -CH2CH(CH3)2 bedeutet, zur Verwendung bei der Behandlung von chronischer obstruktiver Erkrankung der Luftwege oder von Herzleiden.
4. Verbindung der Formel I nach Anspruch 3, worin R -CH2CH2CH3 bedeutet.
EP79850091A 1978-10-20 1979-09-28 Xanthinderivate und pharmazeutische Zusammensetzung zur Verwendung für die Behandlung chronischer Verstopfungen der Atemwege und von Herzkrankheiten Expired EP0011609B2 (de)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AT79850091T ATE2999T1 (de) 1978-10-20 1979-09-28 Xanthinderivate und pharmazeutische zusammensetzung zur verwendung fuer die behandlung chronischer verstopfungen der atemwege und von herzkrankheiten.
DE8181106977T DE2967002D1 (en) 1978-10-20 1979-09-28 Intermediates for the preparation of therapeutically active xanthine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE7810946 1978-10-20
SE7810946A SE7810946L (sv) 1978-10-20 1978-10-20 Metod att behandla kronisk obstruktiv luftvegssjukdom

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP81106977.2 Division-Into 1981-09-05

Publications (4)

Publication Number Publication Date
EP0011609A2 EP0011609A2 (de) 1980-05-28
EP0011609A3 EP0011609A3 (en) 1980-07-23
EP0011609B1 true EP0011609B1 (de) 1983-04-13
EP0011609B2 EP0011609B2 (de) 1988-05-11

Family

ID=20336144

Family Applications (2)

Application Number Title Priority Date Filing Date
EP79850091A Expired EP0011609B2 (de) 1978-10-20 1979-09-28 Xanthinderivate und pharmazeutische Zusammensetzung zur Verwendung für die Behandlung chronischer Verstopfungen der Atemwege und von Herzkrankheiten
EP81106977A Expired EP0045094B1 (de) 1978-10-20 1979-09-28 Zwischenprodukte für die Herstellung therapeutisch wirksamer Xanthinderivate

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP81106977A Expired EP0045094B1 (de) 1978-10-20 1979-09-28 Zwischenprodukte für die Herstellung therapeutisch wirksamer Xanthinderivate

Country Status (8)

Country Link
US (2) US4325956A (de)
EP (2) EP0011609B2 (de)
JP (1) JPS5557517A (de)
AU (1) AU529805B2 (de)
HK (1) HK71486A (de)
IE (1) IE49623B1 (de)
SE (1) SE7810946L (de)
SG (1) SG32486G (de)

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE7810947L (sv) * 1978-10-20 1980-04-21 Draco Ab 3-alkylxanthines
SE8002910L (sv) * 1980-04-18 1981-10-19 Draco Ab 3,8-dialkylxantiner, forfarande for deras framstellning, beredning och metoder for behandling av kronisk obstruktiv luftvegssjukdom och kardiovaskulera sjukdomar
DE3127237A1 (de) * 1981-07-10 1983-01-20 Hoechst Ag, 6000 Frankfurt Magenvertraegliche arzneiformen von xanthinderivaten und verfahren zu ihrer herstellung
US4562194A (en) * 1984-07-31 1985-12-31 Warner-Lambert Company Synergistic non-steroidal anti-inflammatory compounds and compositions thereof
SE8602887D0 (sv) * 1986-06-27 1986-06-27 Draco Ab New chemical method
IT1229195B (it) * 1989-03-10 1991-07-25 Poli Ind Chimica Spa Derivati xantinici ad attivita' broncodilatatrice e loro applicazioni terapeutiche.
EP0407651A3 (en) * 1989-07-10 1991-08-07 J. Uriach & Cia. S.A. Use of 1,3-diisobutyl-8-methylxanthine as a bronchodilator and antiallergy agent
EP0423805B1 (de) 1989-10-20 2000-08-23 Kyowa Hakko Kogyo Kabushiki Kaisha Kondensierte Purinderivate
EP0686157A1 (de) * 1993-02-26 1995-12-13 Schering Corporation 2-benzylpolycyclisch guaninderivate und verfahren zu ihrer herstellung
USRE47351E1 (en) 1999-06-22 2019-04-16 Gilead Sciences, Inc. 2-(N-pyrazolo)adenosines with application as adenosine A2A receptor agonists
US6403567B1 (en) 1999-06-22 2002-06-11 Cv Therapeutics, Inc. N-pyrazole A2A adenosine receptor agonists
US6815446B1 (en) 1999-08-31 2004-11-09 Vanderbilt University Selective antagonists of A2B adenosine receptors
JP3914434B2 (ja) * 1999-08-31 2007-05-16 ヴァンダービルト ユニヴァーシティ Ａ２ｂアデノシン受容体の選択的アンタゴニスト
US20020012946A1 (en) 2000-02-23 2002-01-31 Luiz Belardinelli Method of identifying partial agonists of the A2A receptor
NZ537975A (en) * 2002-07-29 2007-08-31 Cv Therapeutics Inc Method of producing coronary vasodilation without peripheral vasodilation comprising administering at least 10 mcg of at least one A2A receptor agonist
US8470801B2 (en) 2002-07-29 2013-06-25 Gilead Sciences, Inc. Myocardial perfusion imaging methods and compositions
US20050020915A1 (en) * 2002-07-29 2005-01-27 Cv Therapeutics, Inc. Myocardial perfusion imaging methods and compositions
EP1802317A2 (de) * 2004-10-20 2007-07-04 Cv Therapeutics, Inc. Verwendung von a2a-adenosin-rezeptoragonisten
US7732595B2 (en) * 2006-02-03 2010-06-08 Gilead Palo Alto, Inc. Process for preparing an A2A-adenosine receptor agonist and its polymorphs
BRPI0716174A2 (pt) * 2006-09-01 2013-09-24 Cv Therapeutics Inc mÉtodos e composiÇÕes para aumentar a tolerabilidade de paciente durante mÉtodos de imagem do miocÁrdio.
US20090081120A1 (en) * 2006-09-01 2009-03-26 Cv Therapeutics, Inc. Methods and Compositions for Increasing Patient Tolerability During Myocardial Imaging Methods
JP2011502101A (ja) * 2006-09-29 2011-01-20 ギリアード・パロ・アルト・インコーポレイテッド 肺疾患の病歴を有する患者における心筋画像化法
US20080267861A1 (en) * 2007-01-03 2008-10-30 Cv Therapeutics, Inc. Myocardial Perfusion Imaging
BRPI0918962A2 (pt) * 2008-09-29 2015-12-01 Gilead Sciences Inc combinações de um agente de controle de taxa e um antagonista do receptor a-2-alfa para utilização em métodos tomografia computadorizada de multidetectores
JP2016027279A (ja) * 2014-07-02 2016-02-18 日本精工株式会社 冠型保持器及びアンギュラ玉軸受

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1245969B (de) * 1967-08-03 VEB Arzneimittelwerk Dresden, Radebeul Verfahren zur Herstellung von Xanthinderivaten
GB683523A (en) 1948-08-18 1952-12-03 Beecham Res Lab The manufacture of purine derivatives
JPS53890B2 (de) * 1972-04-22 1978-01-12
GB1435916A (en) * 1972-05-11 1976-05-19 Beecham Group Ltd Pharmaceutical weight-reducing compositions
CA1077932A (en) * 1976-03-31 1980-05-20 Berlex Laboratories, Inc. Xanthine compounds and method of treating bronchospastic and allergic diseases
US4089959A (en) * 1976-03-31 1978-05-16 Cooper Laboratories, Inc. Long-acting xanthine bronchodilators and antiallergy agents

Also Published As

Publication number Publication date
EP0045094B1 (de) 1984-05-16
IE49623B1 (en) 1985-11-13
AU529805B2 (en) 1983-06-23
EP0011609A3 (en) 1980-07-23
AU5187279A (en) 1980-05-01
JPS6340167B2 (de) 1988-08-10
EP0011609A2 (de) 1980-05-28
US4804664A (en) 1989-02-14
EP0011609B2 (de) 1988-05-11
SG32486G (en) 1989-12-22
JPS5557517A (en) 1980-04-28
SE7810946L (sv) 1980-04-21
EP0045094A1 (de) 1982-02-03
IE791988L (en) 1980-04-20
US4325956A (en) 1982-04-20
HK71486A (en) 1986-10-03

Similar Documents

Publication Publication Date Title
EP0011609B1 (de) Xanthinderivate und pharmazeutische Zusammensetzung zur Verwendung für die Behandlung chronischer Verstopfungen der Atemwege und von Herzkrankheiten
EP0010531B1 (de) 3-Alkylxanthine, Verfahren zu ihrer Herstellung und Zusammensetzungen zur Benutzung in der Behandlung chronisch verlegter Atemwege und von Herzkrankheiten
US4089959A (en) Long-acting xanthine bronchodilators and antiallergy agents
DE69824632T2 (de) Purinderivate und medikamente, welche dieselben als aktiven bestandteil enthalten
RU2073679C1 (ru) Производные ксантина или их фармацевтически приемлемые соли, способ получения производных ксантина или их фармацевтически приемлемых солей, фармацевтическая композиция
KR850000871B1 (ko) 페닐에탄올아민 유도체의 제조방법
EP0001735B1 (de) Xanthinderivate mit antiallergischer Wirkung und diese enthaltende pharmakologische Zusammensetzungen
US4120947A (en) Xanthine compounds and method of treating bronchospastic and allergic diseases
US4546182A (en) 3,8-Dialkylxanthines
US4031218A (en) 7-(2,3-Dihydroxypropyl-1,3-di-n-propylxanthine and a pharmaceutical composition containing same useful as a bronchial muscle relaxant
US4338319A (en) Method for the treatment of chronic obstructive airway or cardiac diseases
CS221846B2 (en) Method of making the ethanolamine derivatives
JPH11505240A (ja) 減量用薬剤
US3974164A (en) Reserpic acid derivatives
JPH05262770A (ja) 化学的製法

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

PUAL Search report despatched

Free format text: ORIGINAL CODE: 0009013

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LU NL SE

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LU NL SE

17P Request for examination filed

Effective date: 19801222

ITF It: translation for a ep patent filed

Owner name: BARZANO' E ZANARDO ROMA S.P.A.

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): AT BE CH DE FR GB IT LU NL SE

REF Corresponds to:

Ref document number: 2999

Country of ref document: AT

Date of ref document: 19830415

Kind code of ref document: T

ET Fr: translation filed
REF Corresponds to:

Ref document number: 2965208

Country of ref document: DE

Date of ref document: 19830519

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19830713

Year of fee payment: 5

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19830930

PLBI Opposition filed

Free format text: ORIGINAL CODE: 0009260

26 Opposition filed

Opponent name: NAPP LABORATORIES LTD.

Effective date: 19840109

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19840930

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19841026

Year of fee payment: 6

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: AT

Payment date: 19860911

Year of fee payment: 8

PUAH Patent maintained in amended form

Free format text: ORIGINAL CODE: 0009272

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: PATENT MAINTAINED AS AMENDED

27A Patent maintained in amended form

Effective date: 19880511

AK Designated contracting states

Kind code of ref document: B2

Designated state(s): AT BE CH DE FR GB IT LU NL SE

ITF It: translation for a ep patent filed

Owner name: BARZANO' E ZANARDO ROMA S.P.A.

ET3 Fr: translation filed ** decision concerning opposition
NLR2 Nl: decision of opposition
NLR3 Nl: receipt of modified translations in the netherlands language after an opposition procedure
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: AT

Effective date: 19890928

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19890930

Ref country code: BE

Effective date: 19890930

BERE Be: lapsed

Owner name: A.B. DRACO

Effective date: 19890930

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19910806

Year of fee payment: 13

ITTA It: last paid annual fee
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19910930

Year of fee payment: 13

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19920909

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19920914

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19920928

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19920930

Year of fee payment: 14

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19920928

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19930602

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19930929

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19940401

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19940531

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

EUG Se: european patent has lapsed

Ref document number: 79850091.4

Effective date: 19940410

APAC Appeal dossier modified

Free format text: ORIGINAL CODE: EPIDOS NOAPO

APAC Appeal dossier modified

Free format text: ORIGINAL CODE: EPIDOS NOAPO

APAH Appeal reference modified

Free format text: ORIGINAL CODE: EPIDOSCREFNO